CLP1 as a novel player in linking tRNA splicing to neurodegenerative disorders

Wiley Interdiscip Rev RNA. 2015 Jan-Feb;6(1):47-63. doi: 10.1002/wrna.1255. Epub 2014 Aug 20.


Defects in RNA metabolic pathways are well-established causes for neurodegenerative disorders. Several mutations in genes involved in pre-messenger RNA (pre-mRNA) and tRNA metabolism, RNA stability and protein translation have been linked to motor neuron diseases. Our study on a mouse carrying a catalytically inactive version of the RNA kinase CLP1, a component of the tRNA splicing endonuclease complex, revealed a neurological disorder characterized by progressive loss of lower spinal motor neurons. Surprisingly, mutant mice accumulate a novel class of tRNA-derived fragments. In addition, patients with homozygous missense mutations in CLP1 (R140H) were recently identified who suffer from severe motor-sensory defects, cortical dysgenesis and microcephaly, and exhibit alterations in transfer RNA (tRNA) splicing. Here, we review functions of CLP1 in different RNA pathways and provide hypotheses on the role of the tRNA splicing machinery in the generation of tRNA fragments and the molecular links to neurodegenerative disorders. We further immerse the biology of tRNA splicing into topics of (t)RNA metabolism and oxidative stress, putting forward the idea that defects in tRNA processing leading to tRNA fragment accumulation might trigger the development of neurodegenerative diseases.

Publication types

  • Review

MeSH terms

  • Animals
  • Mice
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Neurodegenerative Diseases / physiopathology*
  • Oxidative Stress
  • RNA Splicing*
  • RNA, Transfer / metabolism*
  • RNA-Binding Proteins
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Hexim1 protein, mouse
  • Mutant Proteins
  • RNA-Binding Proteins
  • Transcription Factors
  • RNA, Transfer